Recapturing Disease Response: A Phase II Study of High Dose Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma Who Have Progressed on Standard Dose Carfilzomib

Background:

Carfilzomib (CFZ) is FDA approved at 27 mg/m2 D1,2,8,9,15,16 (except 20 mg/m2 D1,2, of cycle 1) to be given over 10 minutes with an overall response rate (ORR) of 23.7% (Siegel 2012). When CFZ is given as a 30 minute infusion, the dose can be safely escalated to 56 mg/m2, presumably due to a lower Cmax, on a twice weekly schedule with a higher ORR of 55% (Papadopoulos 2014). Our hypothesis was that the disease response of patients who progressed on CFZ 27 mg/m2 could recaptured by dose escalation to 56 mg/m2.

Methods:

Inclusion criteria were progressive disease (PD) at time of study entry, refractory to CFZ 27 mg/m2 without any Grade 3/4 toxicities, > 2 lines of therapy (including bortezomib and an IMID), measurable disease, adequate heme parameters (ANC > 1.0, plt > 50k), and organ function (Cr Cl > 15, cardiac ejection fraction (EF) > 40%).

CFZ was given at 56 mg/m2 Day 1,2,8,9,15,16 over 30 minutes with dexamethasone (dex) 8 mg and ondansetron 8mg premedication. EF was monitored every 2 cycles.

Results:

13 patients received study treatment. The median age was 64.5 (50% greater than age 65 yo) with 4.5 median lines of treatment over 4 years from MM diagnosis. 5 (38%) were high molecular with risk gain of 1q21 by FISH and 3 with concurrent deletion of p53. Also 67, 58, 67, and 100% were refractory to each of the following respectively: lenalidomide, pomalidomide (pom), bortezomib, & CFZ.

Prior to study entry, the median duration of time on CFZ 27 mg/m2 before PD was 136 days. All but 1 patient had been receiving dex 40 mg weekly and 3 had been receiving triplet therapy - 2 with concomitant pom and 1 with ibrutiinib (on a clinical trial).

Of the 12 patients evaluable for efficacy, responses include 1 VGPR, 4 PRs, & 6 SDs, for an ORR of 42% and a median DOR of 6.5 mos. The median PFS was 3.5 mos. Interestingly, 2 of the 3 patients who progressed on CFZ based triplet regimens prior to study entry achieved a PR with CFZ dose escalation.

Grade 3/4 toxicities (regardless of drug attribution) were primarily heme, with neutropenia (36%), thrombocytopenia (8%) and anemia (22%) respectively. Grade 3/4 nonheme AEs included 4 hypertension (HTN), 1 acute dyspnea, 1 ggt elevation, 1 back pain and 1 leg pain. When ggt was added on to screening labs for the patient with grade 4 ggt elevation prompting study discontinuation, it was noted to be elevated to grade 3 even at baseline.

Of the 4 patients with Grade 3/4 HTN, 1 required dose CFZ modification but the remaining 3 were classified as grade 3 only due to the addition of an anti-HTN medications and did not require any CFZ dose modifications. HTN in one these 3 patients was also was in the setting of bone pain and PD. In the 4 patients with serial measurements of brain naturetic peptide (BNP), there were no changes. Similarly, EF was monitored on study for all patients and there were no decreases in EF or symptoms of CHF.

Conclusions:

Consistent with previous data, including from the Endeavor study, CFZ 56 mg/m2 is efficacious and well tolerated with manageable HTN. Even in this heavily pretreated population refractory to CFZ 27 mg/m2 and dex 40 mg weekly refractory and with high molecular risk features, dose escalation of CFZ to 56 mg/m2 with only dex 16 mg weekly was able to recapture disease response at ORR and PFS that have already surpassed the preplanned futility analysis. By avoiding early dose escalation of those that may be at risk for likely idiosyncratic side effects, both safety and lower cost may be maximized. These findings support enrollment to the ongoing SWOG S1304 randomized study comparing CFZ 27 and 56 mg/m2.